For decades, immunotherapy has exclusively relied on in vivo administration of pharmacological preparations aiming at either stimulating (i.e. vaccines) or dampening (i.e. immunosuppressive drugs) patients' immune responses. Based on promising results obtained in animals models, the concept of ex vivo manipulation of immune cells for retransfer as cell therapy: “adoptive cell therapy” (ACT), has progressively emerged1,2. Finally, the demonstration in the late 80's that the transfer of ex vivo expanded tumor-infiltrating T lymphocytes to patients with melanoma could led to cancer regression paved the way for the translation of ACT to the clinic3. ACT is currently considered as a central strategy to treat severe chronic conditions as diverse as viral infections, cancers, autoimmune diseases, allograft rejection or graft versus host disease (218 trials currently registered on https://clinicaltrials.gov/).
Much of initial experimental and clinical studies in ACT have focused on cytotoxic CD8+ T cells because of their remarkable ability to kill tumors or virus-infected cells2,4-7. However, attention has progressively shifted to helper CD4+ T cells that are endowed with a much wider spectrum of functions2,8,9. CD4+ T cells are indeed: i) very efficient for tumor and viral destruction through direct cytotoxicity and promotion of cytotoxic CD8+ T cells responses10-14, ii) necessary for the generation of protective antibody-responses15, iii) endowed with unique immune regulatory properties in addition to their aptitudes to promote effector responses16. The versatility of CD4+ T cells is due to their plasticity, which allows them to polarize into various functional subsets according to the microenvironment in which they are activated16.
Importantly, several experimental studies have illustrated that ACT was more efficient and associated with fewer side effects when antigen-specific CD4+ T cells were used instead of polyclonal CD4+ T cells2,8,9,17. Two recent studies have validated this concept in the clinic. First, ex vivo-expanded autologous CD4+ T-cell clones specific for a given melanoma-associated antigen were able to induce durable clinical remission in a patient with refractory metastatic melanoma18. Second, adoptive transfer of CD4+ T cells recognizing a unique tumor epitope could mediate regression of a metastatic epithelial cancer19. Such antigen-specific CD4+ T cells are however rare and need to be specifically expanded for ACT20. Nanobiotechnology represents a powerful tool to reach this crucial objective21-28.
Physiologically, clonal expansion of antigen-specific CD4+ T cells requires engagement of the T cell antigen-specific receptor (TCR) by the antigen-class II major histocompatibility complex (MHCII) on the surface of antigen-presenting cell (APC). Although reports have shown that it was possible to expand ex vivo antigen-specific T cells with artificial antigen presentation by cell-free substitutes, these emerging technologies still warrant preclinical and clinical validations21,29. Current clinical approaches aiming at expanding CD4+ T cells clones for ACT rather rely on autologous APCs that can be reliably used to confer optimal therapeutic features to T cells before infusion18,19. Dendritic cells (DCs) are professional APCs that can be readily pulsed with any antigens and used as stimulators of antigen-specific CD4+ T cells30. Yet, implementation in practice is difficult because DCs are too rare to be directly purified from peripheral blood. Instead, bone marrow or blood progenitors must be matured in culture during several days before being used as T cells activators. This procedure increases the costs and leads to inconstant yields31-34. Furthermore, the number of mature DCs that can be obtained from these culture is limited because mature DCs stop to divide and become less effective at presenting antigen after 2 to 3 weeks in culture (in fact, it is generally accepted that the final number of DCs cannot be expanded beyond the number of starting progenitors)33,34. In contrast, B cells are “ready to use” APCs, which are abundant in the circulation (up to 0.5×106 cells/mL) and can be further exponentially expanded in vitro without loss of antigen-presenting functions31-33. B cells therefore represent an unrestricted source of autologous APCs for ACT31,32. However, the use of B cells as stimulators of antigen-specific CD4+ T cells is made problematic due to their inability to present non-cognate antigens35. In contrast with DCs, which can engulf any antigen by phagocytosis, B cells can only internalized cognate antigen36-38. It is indeed the binding of the specific antigen to B cell's surface immunoglobulins (B cell receptor, BCR) that triggers: (i) the activation signal required for the acquisition of potent antigen-presenting functions and (ii) the antigen internalization in endosome where antigen is processed and loaded in MHCII for presentation to CD4+ T cells. Antigen-specific B cells are too rare to be used in ACT.